Influenza viruses are negative-sense, single-stranded RNA viruses that infect the upper, and occasionally the lower, respiratory tracts In the US. Illness from infections by influenza virus has caused an average of approximately 36,000 deaths from 1990-1999 and 226,000 hospitalizations during 1979-2001 (Thompson, W. W., et al. PMID: 15367555), (Thompson, W. W., et al. PMID:12517228). Influenza A more ..

Influenza viruses are negative-sense, single-stranded RNA viruses that infect the upper, and occasionally the lower, respiratory tracts In the US. Illness from infections by influenza virus has caused an average of approximately 36,000 deaths from 1990-1999 and 226,000 hospitalizations during 1979-2001 (Thompson, W. W., et al. PMID: 15367555), (Thompson, W. W., et al. PMID:12517228). Influenza A viruses (IAV), which also infect a wide number of avian and mammalian species, pose a considerable public health burden with epidemic and pandemic potential. This is particularly evident with the new strain of "swine flu virus" which emerged recently in Mexico and spread to different parts of the North America (MMWR Morb Mortal Wkly Rep PMID:19390508). The most devastating IAV pandemic occurred in 1918 which resulted in approximately 30 million deaths worldwide (Reid, A. H., et al. PMID: 11226857).

Antivirals are widely used in treatment of epidemic and pandemic IAV infections. Certainly, the lack of availability of vaccines early in IAV pandemics has driven the search for effective antivirals. One potential and largely unexplored IAV target is to disarm viral proteins that modulate the host's antiviral response. NS1A protein is a critical viral protein in this regard. During viral infection, infected cells of the host mount a potent and diverse antiviral defense response to prevent virus proliferation (Randall, R. E., et al. PMID: 18089727). To perpetuate, IAV have evolved multiple mechanisms to circumvent these host defense mechanisms. Strategies include those which are strain-specific such as increased replication speed (Grimm, D., et al. PMID: 17426143), (Kurokawa, M., et al. PMID: 10202186) or those that reduce sensitivity to host-cell antiviral defense mechanisms (Dittmann, J., et al. PMID: 17970694). The NS1A protein inhibits the interferon-alpha-beta-induced 2'-5'-oligo synthetase. Drugs that target the NS1A double-stranded (ds) RNA binding domain would inhibit IAV replication.

The N terminus of the NS1A protein (NS1A) of IAV is a highly conserved, multifunctional viral protein which interacts with host dsRNA (Cheng, A., et al. PMID: 18813227). We have developed an AlphaScreen (Perkin Elmer)-based 1536-well high throughput screen (HTS) for NS1A to identify small molecule inhibitors of the dsRNA binding activity. Identification of probes for this activity would provide valuable tools for probing its dsRNA binding function within the cell. Further, this domain could also serve as a target for antiviral drug discovery.